The first successful cardiopulmonary bypass procedure was performed in 1953 by John Gibbon at the Thomas Jefferson University Hospital in Philadelphia. Today, hundreds of thousands of procedures are performed worldwide every year.
Priming solutions for cardiopulmonary bypass (CPB), also known as extra corporeal circulation (ECC), are used to fill up sections of a bypass circuit, such as the tubing, the pump and the reservoir. The main purpose of the solution is to remove air from the system which could otherwise cause air emboli when the circuit is connected to a patient.
In the early days of CPB, donor blood was used to prime the circuit, the patient's own blood being the best solution to perfuse. However, this practice has largely been abandoned today, due to cost, lack of blood and the side effects that donor blood transfusion has been associated with, such as risk of transmitting infectious disease and immunosuppression.
In use, the patient is connected to the circuit, and the priming solution is mixed with the patient's blood. This causes significant dilution of the blood, which can be harmful to the patient. It is therefore important to reduce the harmful effects of the haemodilution and the priming solution. The blood volume is related to the size of the patient, a smaller patient having less volume and a larger patient having more volume. However, the volume of the priming solution depends largely on the circuit used. Generally, 1.5 to 2 liters of priming solution are used to fill the system, regardless of the patient's size.
Fluid distribution in humans is divided between the extracellular fluid (ECF) and the intracellular fluid (ICF). The ECF is further distributed between the vascular space, which contains about 25% of the total ECF volume, and the interstitial space, which contains about 75% of the total ECF volume (Griffel et al., 1992). Isotonic solutions such as Ringer's lactate have a similar osmotic pressure to plasma and addition to the circulation does therefore not form a water potential gradient. This means that after dilution of the blood with an isotonic crystalloid solution, 75% of the solution will remain interstitially and 25% will remain in the vasculature (Griffel et al., 1992). The more crystalloid the solution that is given, the more interstitial oedema forms.
Despite the long history of the procedure and its common use, there is still no consensus as to which priming solution, crystalloid or colloidal, to use (Boldt et al., 2009, Gu et al., 2005). Crystalloid solutions used for CPB are generally balanced salt solutions such as saline and Ringer's lactate or dextrose/mannitol solutions. Often they contain a mixture of salt and/or sugars. A hypertonic saline has been used for CPB (McDaniel et al., 1994). Such a hypertonic crystalloid solution creates a water potential gradient, thereby causing water to move from the interstitial compartment to the vasculature, due to the high osmotic pressure it provides. However, the effect is soon lost as the electrolytes move to the interstitium.
Colloidal solutions are generally a mixture of a balanced salt solution and a large molecule, which cannot easily enter the interstitium and therefore remains longer in the vasculature, thereby providing an oncotic pressure. Large molecules that have been used over the years in colloidal priming solutions include albumin, gelatine, hydroxyethyl starch (HES) and, to some extent, dextrans. These molecules provide a colloidal osmotic pressure or a colloidal oncotic pressure. The terms “colloidal osmotic pressure” and “colloidal oncotic pressure” are used interchangeably within this application. In practice, this means that a hyperoncotic colloidal solution administered to the vasculature brings water out from the interstitial compartment into the vasculature. This changes the distribution between the ECFs, with less of the fluid residing in the interstitial compartment. Hence, a hyperoncotic solution increases the total volume in the vasculature by a greater amount than the total volume being given. For example, a 25% albumin solution increases the volume in the vasculature almost five times the given volume (Griffel et al., 1992). Normal human oncotic pressure in the plasma is about 28 mmHg and a hyperoncotic solution must provide a higher oncotic pressure than this. The higher the oncotic pressure, the more water is shifted from the interstitium to the vasculature.
Oedema is therefore reduced with hyperoncotic solutions and as a consequence the vascular resistance decreases, providing improved micro-circulation and reduced risk of hypo-perfusion. The brain is one of the regions that benefits the most from this change. Cognitive dysfunction post-cardiopulmonary bypass for open heart surgery has been reported to be as high as 70% (Iriz et al., 2005). An improvement in cognitive function was shown when a colloidal solution (HES) was used compared to a crystalloid solution (Iriz et al., 2005).
Simple balanced salt solutions like Ringer's lactate or Ringer's acetate are sometimes used. These simple solutions provide a low oncotic pressure to the circulating blood, which leads to water leaking into the interstitial spaces and tissue, thereby forming oedema. This can be avoided by using a hyperosmotic solution. However, to maintain a stable oncotic pressure there is a need for a colloidal solution.
There are new cardiopulmonary bypass machines on the market that work with much less priming volume. These reduced size systems are expensive and their usage may lead to increased risks as the reduced volumes give the perfusionist less reserve volume to work with, thereby increasing the risk of air being introduced to the vasculature. They are therefore only indicated during certain circumstances.
Endogenous albumin is the major protein in plasma, providing about 80% of the oncotic pressure in a healthy person. It is, of course, the optimal molecule to use when endogenous and during normal body function. However, if non-endogenous albumin is used, it is expensive and the risk of transmitting infectious diseases can never be completely ruled out. Blood derived products can also cause immunosuppression (Spiess, 2001), and administration of human albumin does carry a small risk of anaphylactic reactions.
Gelatines are modified collagen derivatives. The collagen is generally obtained from bovine material. The gelatines used are urea-bridged or otherwise connected heterogeneous peptide polymers. Apart from the apparent risk of transmission of infectious disease, the modified gelatines are known to cause anaphylactic reactions. The reactions can either be due to histamine release or can be antibody-mediated.
Hydroxyethyl starch (HES) is a molecule derived from amylopectin. Amylopectin is a highly branched glucose polymer and it is modified to HES through hydroxyethyl substitutions. The substitutions make it less vulnerable to amylase degradation and therefore more stable in the blood. HES is a heterogeneous mixture of particles of different sizes and degrees of substitution. The smaller molecules are rapidly excreted in the urine, while the largest molecules can be taken up by tissue and remain in the body for weeks, months and even years. There are different versions of HES available on the market, varying in molecular size distribution, side chains and degree of substitution. Administration does carry a risk of anaphylactic reactions, as well as disturbances in the complement and coagulation systems. An underestimated side effect is persistent itching, believed to be related to the accumulation of the largest molecules in the body. The onset of the itching is often delayed and therefore it is not always associated with the use of HES.
Dextran is a heterogeneous, bacterially-produced glucose polymer with molecular weights ranging from thousands to millions of Daltons. However, commercially produced dextran is generally hydrolysed to smaller fractions. Commercial dextrans often have a mean molecular weight of 1, 40, 60 or 70 kDa. The actual weight of individual dextran molecules in each commercial sample may vary. For example, a Dextran 40 sample will include molecules with a range of weights, but the mean molecular weight will be 40 kDa. Dextran 1 is not used to create oncotic pressure in colloidal solutions due to its small mean molecular size. Dextrans are much less branched than HES molecules and are therefore also more extended than HES or albumin, which are more globular. Dextran molecules are also not charged, unlike proteins. Dextrans can be modified in various ways to alter their properties. Such modified dextrans are contemplated for use in the solution as disclosed.
Despite the fact that dextrans are considered pharmacologically inert, they provide various effects on the immune system as well as the coagulation system. The exact mechanisms involved are not known, but it is thought to be due to steric effects. For example, dextran is known to reduce thrombogenesis and it has been used instead of or in combination with the anti-coagulant heparin for this purpose. Many coagulation factor interactions have been hypothesized, but the most well documented interactions are with platelets and Factor VIII (Grocott et al., 2002).
The properties of dextran make it very favourable for use in colloidal priming solutions. It is cheap compared to albumin, and it has better coating properties than HES. It also has been shown to reduce ischemic reperfusion injury, and it is easily extracted from the body.
Dextran does have a risk of anaphylactic reaction. However, this risk can be reduced through pre-administration of a dextran with a low molecular weight, such as Dextran 1. This pre-administration means that dextran has a smaller risk of anaphylactic reaction when compared with that for the other large molecules. It is thought that the small dextran molecules bind to the immunoglobulins involved in the reaction, thereby preventing aggregation of the immunoglobulins and an anaphylactic reaction (U.S. Pat. No. 4,201,772). Due to the small molecular weight of Dextran 1, a small dose in terms of grams outnumbers the larger molecules from colloidal preparations, thereby creating effective prophylaxis.
Dextran is known to increase capillary flow. This is achieved partly through reducing the viscosity of the blood and the oncotic action, thereby reducing swelling and opening the capillaries, and partly because it prevents leukocytes sticking to the microvasculature, which would otherwise cause further narrowing of the vessels.
However, the main reason that dextrans are not more widely used in CPB priming solutions is the dose dependent risk of bleeding on their administration. It may be the dextran's effect on the coagulation system which increases the risk of bleeding when used in sufficient concentrations to provide a functional hyperoncotic pressure. Bleeding is, of course, of major concern during open heart surgery and cardiopulmonary bypass. An increased risk of excessive bleeding could therefore outweigh the positive effects that the colloidal solution could provide.
The increased coagulopathy with dextran compared to HES is described in Tigchelaar et al., 2010, which indicates that “ . . . hydroxyethyl starch can not be labelled as an antithrombotic agent like dextran.”. Petroianu et al., 2000 indicates that “ . . . we suggest that dextran (especially 10% Dextran 40) and HES preparations should be used with caution when bleeding would potentially be of serious consequence to the patient”. Although the authors of these papers have different views on HES, which could likely be explained by the different preparations used, they are consistent in terms of the risks with dextran.
Dextrans are sometimes used in resuscitation solutions for trauma patients because of their beneficial properties. Due to risk of bleeding, there is a set limit of 1.5 g dextran per kg body weight and 24 hours. This limit has not been specified for use of dextrans in colloidal priming solutions for CPB. However, bleeding is even more of a concern in relation to CPB, as the patient is already at risk of bleeding complications due to heparinisation and the procedure as such. Therefore, it is argued that the recommended dose limit for dextrans may be lower than 1 to 1.5 g/kg body weight and 24 hours during CPB (Gu et al., 2006).
The dose dependency is of concern as CPB is a standardised procedure that does not take the body weight of the patient into consideration. A patient of 50 kg receives as much priming solution as a patient of 100 kg, resulting in a doubled dose in the smaller patient. A further point is that the administration of the whole dose during CPB priming is instant and not delayed over 24 hours.
Although much of the research referred to in relation to fluid distribution and effects of colloids and crystalloids comes from the field of resuscitation and not CPB, the differences between these two fields must be remembered. The main difference is that in resuscitation, a lost blood volume is being replaced by an infused fluid with the aim of increasing the volume in the vasculature and thereby restoring blood pressure. During CPB the priming solution is not used to replace lost volume, but instead it adds circulating volume to be able to fill not only the vasculature, but also the extra corporeal circuit, with fluid. Another difference is that CPB in itself causes changes to the inflammatory and coagulation pathways, partly through contact with the bypass circuit surfaces. Heparin is also used in conjunction with CPB, further affecting the coagulation pathway.
Low concentration dextran solutions that do not provide functional hyperoncotic pressure have been used for priming of CPB circuits, as discussed below.
Lancon et al., 1975 used a priming solution consisting of a mixture of 1.5 liters of 3.5% Dextran 40 and 0.5 liters of Ringer's solution. The solution works similarly to an albumin containing solution. The dextran solution used contains a relatively low Dextran 40 concentration, which may not provide a functional hyperoncotic pressure. There is no mention of the addition of a lower molecular weight dextran.
Mellbye et al., 1988 describe the use of 1.5 liters of Macrodex (10% Dextran 70) in a priming solution with a total volume of 2.4 liters solution for CPB. The study aimed to investigate the effect on the complement system with plasma or dextran as the primer. The paper states that dextran is known to activate the alternative pathway of complement. Bleeding is not discussed and there is no mention of the addition of a lower molecular weight dextran.
Lee et al., 1975 is a clinical study that compares results with three different priming solutions. Solution 1 is a crystalloid solution, solution 2 is Ringer's lactate with 1% Dextran 40 and solution 3 is an HES solution. The dextran solution used contains a relatively low Dextran 40 concentration and there is no mention of addition of a lower molecular weight dextran.